Diaphragm dysfunction caused by sphingomyelinase requires the p47(phox) subunit of NADPH oxidase.
Diaphragm dysfunction caused by sphingomyelinase requires the p47(phox) subunit of NADPH oxidase.
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DOI：
10.1016/j.resp.2014.10.011
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发表时间：
2015-01-01
影响因子：
2.3
通讯作者：
Ferreira, Leonardo F.
中科院分区：
文献类型：
--
作者：
Bost, Elaina R.;Frye, Gregory S.;Ahn, Bumsoo;Ferreira, Leonardo F.
鞘磷脂酶(SMase)活性在炎症状态下升高，并可能在这些情况下导致肌肉无力。外源性sMase以氧化剂依赖的方式抑制肌力。然而，sMase刺激导致肌肉无力的途径尚不清楚。在非肌肉细胞中，sMase激活NADPH氧化酶的NOX2亚型，这需要p47Phox亚基来发挥酶的作用。我们从遗传学和药理学角度以p47Phox为靶点(Apocynin)来研究NADPH氧化酶在sMase诱导的氧化剂增加和横隔膜虚弱中的作用。SMASE增加胞浆氧化剂(任意单位：对照203±15，SMase 276±22；P<；0.05)，抑制野生型小鼠的最大力量(N/cm2：对照20±1，SMase 16±0.6；P<；0.05)。然而，p47Phox缺陷小鼠不受氧化剂增加(任意单位：对照组217±27，sMase 224±17)和sMase引起的力量丧失(N/cm2：对照组20±1，sMase 19±1)的保护。Apocynin可部分阻止sMase引起的力量减弱(n=3只小鼠/组)。因此，我们的研究表明，NADPH氧化酶在氧化剂介导的由sMase引发的横隔膜虚弱中起着重要作用。这些观察为NADPH氧化酶调节骨骼肌功能提供了进一步的证据。
Sphingomyelinase (SMase) activity is elevated in inflammatory states and may contribute to muscle weakness in these conditions. Exogenous SMase depresses muscle force in an oxidant-dependent manner. However, the pathway stimulated by SMase that leads to muscle weakness is unclear. In non-muscle cells, SMase activates the Nox2 isoform of NADPH oxidase, which requires the p47phox subunit for enzyme function. We targeted p47phox genetically and pharmacologically (apocynin) to examine the role of NADPH oxidase on SMase-induced increase in oxidants and diaphragm weakness. SMase increased cytosolic oxidants (arbitrary units: control 203±15, SMase 276±22; P < 0.05) and depressed maximal force in wild type mice (N/cm2: control 20±1, SMase 16±0.6; P < 0.05). However, p47phox deficient mice were protected from increased oxidants (arbitrary units: control 217±27, SMase 224±17) and loss of force elicited by SMase (N/cm2: control 20±1, SMase 19±1). Apocynin appeared to partially prevent the decrease in force caused by SMase (n = 3 mice/group). Thus, our study suggests that NADPH oxidase plays an important role on oxidant-mediated diaphragm weakness triggered by SMase. These observations provide further evidence that NADPH oxidase modulates skeletal muscle function.
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